The timing of treatment initiation in asymptomatic HIV-infected patients is a critical decision. The available evidence regarding early versus late initiation of HAART is limited by lead time bias and poor control of confounding, leaving patients and physicians to speculate on the risks and benefits of beginning treatment. The purpose of this study is to produce precise, unbiased estimates of the additional months or years of survival that patients can expect from starting HAART at their present stage of HIV disease compared to delaying treatment initiation. We will use data from the CASCADE Collaboration which is a prospective, observational cohort of HIV-infected adults in Europe and Australia with well-estimated dates of seroconversion. Cox proportional hazards, marginal structural models, and spline-based hazards regression will be used to produce adjusted estimates of the time to first AIDS diagnosis or death in those patients who were treated with HAART in a given CD4 strata compared to those who deferred treatment. We will evaluate age, gender, HIV exposure group, HIV RNA, rate of CD4 decline, CD4 nadir, duration of infection, seroconversion illness, HIV test interval, source cohort and calendar period as potential confounders. Antiretroviral therapy carries the danger of serious side effects and toxicities, the inconvenience and expense of daily life-long regimens, and the unknown impact on future treatment options. Likewise, deferring therapy may result in irreparable damage to the immune system that might otherwise have been preserved by therapy, thereby extending life. Clear guidelines based on methodologically sound research are needed to inform patient and healthcare provider decisions about when to embark on antir.etroviral treatment so as to maximize the benefit that HAART can offer.